The goal of this application is to study placebo analgesia in headache-free migraine patients using simultaneous measures of brain function (fMRI) and -opioid receptor availability (11C-carnetanil PET). By studying the placebo effect in a relevant clinical population, we will obtain unique data on brain function, chemistry, and, critically, their interaction. It is well established that persistent pain changes bothstructure, function, connectivity and chemistry of the brain. Moreover, ongoing chronic pain influences experimental pain, making interpretations of results derived from patient populations difficult. Are differences due to the altered brain, or due to the ongoing experience of chronic pain? By studying migraine patients in the inter-ictal (headache free) state, we can rule out the latter and describe placebo analgesia in pain-altered (but pain free) brains, as compared to healthy brains. By employing simultaneous fMRI and PET imaging, we will be provide novel data on how brain blood flow changes (fMRI) and endogenous opioid release (PET) interact to create the subjective experience of placebo pain reduction. This will provide a new level of understanding of placebo responses, and lay a foundation for studying and developing predictive biomarkers for clinical placebo responses. PUBLIC HEALTH RELEVANCE: Current neurobiological models of the placebo response rely on studies of either brain function or chemistry in healthy subjects. Chronic pain changes the brain and placebo responses in patients may have different mechanisms. We will study placebo responses in migraine patients and measure brain function and chemistry simultaneously.